Chemistry:Pitolisant

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Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy.[1] It is an inverse agonist of the histamine H3 receptor.[1] It represents the first commercially available medication in its class, so that the U.S. Food and Drug Administration (FDA) declares it a first-in-class medication.[2][3] Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.[4] It was approved by the European Medicines Agency (EMA) in March 2016 for narcolepsy with or without cataplexy, and for excessive daytime sleepiness by the FDA in August 2019.[5] The most common side effects include difficulty sleeping, nausea, and feeling worried.[6]

Medical uses

Pitolisant is indicated in adults for the treatment of narcolepsy.[1][7] Narcolepsy is a chronic sleep disorder that causes overwhelming daytime drowsiness.[7] Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults with obstructive sleep apnea.[8][9]

Side effects

The most common side effects include insomnia, headache, nausea, anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo, dyspepsia, and heartburn.[7] Rare but serious side effects are abnormal weight loss and spontaneous abortion.[7]

Pharmacology

Pitolisant is an inverse agonist of the histamine H3 autoreceptor. The H3 autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.[10] By preventing the binding of endogenous histamine at the H3, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.[11]

Pitolisant is a drug that belongs to the class of central nervous system (CNS) stimulants.[12][13][14][15] Pitolisant is also considered a eugeroic, which means that it promotes wakefulness and alertness. Eugeroics are different from traditional CNS stimulants such as amphetamine in that they have fewer side effects and lower abuse potential. Pitolisant is the first eugeroic drug that acts by blocking the histamine H3 autoreceptor, which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.[16][17][18]

Binding affinities[19]
Target Ki Activity
H3 150 nM Inverse agonist
σ1 <10 nM Agonist
σ2 52 nM Antagonist
D3 382 nM Antagonist
5-HT2A 544 nM Antagonist

Pitolisant has been demonstrated to exhibit high affinity for sigma-1 and sigma-2 receptors, as well as moderate affinity for 5-HT2A and D3 receptors. There exist conflicting findings relating the intrinsic activity of pitolisant at the 5-HT2A receptor.[20]

Pharmacokinetics

Pitolisant is readily absorbed when taken by mouth and reaches peak blood concentrations approximately 3 hours after administration. The biological half-life of Pitolisant ranges from 10 to 12 hours.[11]

History

Pitolisant is marketed in the European Union by Bioprojet Pharma.[7] It was approved for medical use in the European Union in March 2016 by the European Medicines Agency (EMA).[5][7]

The U.S. Food and Drug Administration (FDA) approved pitolisant for excessive daytime sleepiness in participants with narcolepsy based primarily on evidence from two trials (Trial 1/NCT01067222, Trial 2/NCT01638403).[6] An additional trial (Trial 3/NCT01800045), in which participants with a different type of narcolepsy were exposed to the same dose of pitolisant, was used to add data for evaluation of side effects.[6] The trials were conducted in Europe and South America.[6]

The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness.[6] Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks.[6] For participants receiving pitolisant, the dose could be increased during the first three weeks but had to remain the same for the next five weeks.[6] Neither the participants nor the healthcare providers knew which treatment was being given during the trial.[6]

The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants.[6] To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS).[6] The ESS asks participants to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television).[6] Participants rate each item from zero (would never doze) to three (high chance of dozing).[6]

Pitolisant was approved by the FDA in August 2019.[5][6] It was granted orphan drug designation for the treatment of narcolepsy,[21] fast track designation for the treatment of excessive daytime sleepiness and cataplexy in people with narcolepsy, and breakthrough therapy designation for the treatment of cataplexy in people with narcolepsy.[22]

Society and culture

Pitolisant is approved in the European Union and the United States to treat narcolepsy, and is not a controlled substance in these countries. Still, long-term studies comparing the effectiveness and tolerability of pitolisant with modafinil or sodium oxybate are lacking. </ref>[23]

References

  1. ↑ 1.0 1.1 1.2 "Wakix- pitolisant hydrochloride tablet, film coated". 6 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8daa5562-824e-476c-9652-26ceef3d4b0e. 
  2. ↑ "New Drug Therapy Approvals 2019". 31 December 2019. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019. 
  3. ↑ "FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy". 16 August 2019. https://www.pharmacytimes.com/news/fda-approves-pitolisant-for-daytime-sleepiness-in-patients-with-narcolepsy. 
  4. ↑ "Pitolisant: First Global Approval". Drugs 76 (13): 1313–1318. September 2016. doi:10.1007/s40265-016-0620-1. PMID 27438291. 
  5. ↑ 5.0 5.1 5.2 "A Comprehensive Review of Novel FDA-Approved Psychiatric Medications (2018-2022)". Cureus 16 (3). March 2024. doi:10.7759/cureus.56561. PMID 38646400. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 "Drug Trials Snapshots: Wakix". 14 August 2019. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-wakix.  Public Domain This article incorporates text from this source, which is in the public domain.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Wakix EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/wakix.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ↑ "Ozawade EPAR". 20 May 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade. 
  9. ↑ "Evaluating pharmacological treatments for excessive daytime sleepiness in obstructive sleep apnea: A comprehensive network meta-analysis and systematic review". Sleep Med Rev 76. August 2024. doi:10.1016/j.smrv.2024.101934. PMID 38754208. 
  10. ↑ "Identification of two H3-histamine receptor subtypes". Molecular Pharmacology 38 (5): 610–613. November 1990. doi:10.1016/S0026-895X(25)09479-9. PMID 2172771. https://molpharm.aspetjournals.org/content/38/5/610. Retrieved 10 April 2023. 
  11. ↑ 11.0 11.1 "pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy". Health Psychology Research 10 (3). 30 May 2022. doi:10.52965/001c.34222. PMID 35774905. 
  12. ↑ "Pitolisant". National Institute of Diabetes and Digestive and Kidney Diseases. 2012. https://www.ncbi.nlm.nih.gov/books/NBK573784/. 
  13. ↑ "Central Nervous System (CNS) Stimulants". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 22 January 2012. https://www.ncbi.nlm.nih.gov/books/NBK548702/. Retrieved 22 January 2024. 
  14. ↑ "Pitolisant Uses, Side Effects & Warnings". https://www.drugs.com/mtm/pitolisant.html. 
  15. ↑ "List of CNS stimulants + Uses & Side Effects". https://www.drugs.com/drug-class/cns-stimulants.html. 
  16. ↑ "Pitolisant (Wakix) for Narcolepsy". JAMA 326 (11): 1060–1061. 21 September 2021. doi:10.1001/jama.2021.1349. PMID 34546302. 
  17. ↑ "The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use". Sleep Medicine 33: 125–129. 1 May 2017. doi:10.1016/j.sleep.2017.01.002. PMID 28449891. 
  18. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pmid31997137
  19. ↑ Shah, Dhara (July 12, 2019). "OPDP Labeling Comments for WAKIX® (pitolisant) tablets, for oral use". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000OtherR.pdf. 
  20. ↑ Solages, Martine. "Wakix (Pitolisant)". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000MedR.pdf. 
  21. ↑ "Pitolisant Orphan Drug Designations and Approvals". 17 May 2010. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=307210. 
  22. ↑ "Harmony's pitolisant granted breakthrough and fast track designations". 22 May 2018. https://www.pbiforum.net/mag/featured/harmonys-pitolisant-granted-breakthrough-and-fast-track-designations/. 
  23. ↑ "Evaluating pitolisant as a narcolepsy treatment option". Expert Opinion on Pharmacotherapy 22 (2): 155–162. February 2021. doi:10.1080/14656566.2020.1817387. PMID 32941089. 
  • Clinical trial number NCT01067222 for "Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy (Harmony1)" at ClinicalTrials.gov
  • Clinical trial number NCT01638403 for "Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy." at ClinicalTrials.gov

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